DECEMBER 2016

Researchers at University College London and Mount Sinai Hospital in New York have identified a new genetic risk factor for Crohn’s disease in the Ashkenazi Jewish population. The work was published in two articles in the leading journal Gastroenterology.

The UCL group studied two large Ashkenazi families with multiple affected individuals whilst the Mount Sinai group studied approximately 1,500 unrelated affected individuals and 2,500 unaffected Ashkenazi Jewish individuals.

By sequencing DNA and using computational methods, both groups independently narrowed in on the identical genetic variant in the gene CSF2RB. This variant was found in approximately 4% of healthy Ashkenazi individuals but in approximately 6% of those with Crohn’s disease.

CSF2RB plays an important part in the body’s response to infection by activating immune cells. White blood cells from individuals with the Crohn’s disease associated genetic variant were found to respond differently.

The identification of this new gene for Crohn’s disease emphasises an essential role for a new biological pathway which, when abnormal, may contribute to Crohn’s disease. It is early days, but this is a potential target for new treatments. This also goes a little bit of the way to explaining why Crohn’s disease may be more common amongst the Ashkenazi population.

NOVEMBER 2015

Promising results for a new drug for Crohn’s disease

Early this year, a study testing a new drug for Crohn’s disease called Mongersen demonstrated encouraging results. The findings were published in the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1407250). Mongersen, which is taken in tablet form, acts via a molecule called SMAD7 to alter the activity of an important regulator of the immune system, known as TGF-beta. The study, undertaken in Italy, involved 160 patients with moderate or severe Crohn’s disease. The patients were randomly allocated to receive one of three doses of Mongersen or a placebo for two weeks. A validated clinical score summarising Crohn’s disease activity was used to determine the effect of the drug.

After the two week treatment period, 10% of patients receiving the placebo were in remission as compared with 12%, 55% and 65% of the patients receiving increasing doses of Mongersen. These are encouraging results with the higher doses having much larger effects than those seen in studies for Infliximab (Remicade), Adalimumab (Humira) or Vedolizumab (Entyvio). Another important finding was that a large proportion of patients receiving the higher doses of Mongersen remained in remission for almost three months after the two week treatment period. There were a number of important limitations of the study, such as the criteria used to decide which patients should be included, and larger follow up studies will be required to confirm the findings. Nonetheless, these are exciting results and further studies of Mongersen will be anxiously awaited.

The role of genetics in determining Inflammatory Bowel Disease subtype

A recent study undertaken by a large international collaboration of researchers and published in The Lancet (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00465-1/abstract) has investigated the relationship between genetic factors and Inflammatory Bowel Disease (IBD) subtype in over 30,000 patients from 16 countries. This study, the largest such undertaken to date, suggests that Crohn’s disease and ulcerative colitis are on a continuum, with large bowel Crohn’s disease being genetically intermediate between ulcerative colitis and small bowel Crohn’s disease.  This is in contrast to the traditional distinct classification of the diseases.

Differences in genetic risk factors between the disease subtypes suggest that there is, at least in part, a genetic basis that determines which part of the bowel is affected by IBD and the age of onset. The results also suggest that the location of the bowel affected is the major determinant of the subsequent course the disease takes. In the vast majority of cases, genetic risk scores could not predict either who may develop IBD, or which type.

However, it was found that in a very small proportion of IBD patients, the genetic risk scores could help identify misdiagnoses in patients whose genetic data were at the extreme end of the distribution and were inconsistent with their labelled subtype. This may be of value in preventing possibly unwarranted surgery.  Whilst this research has reinforced the importance of genetics in IBD, it is clear that the genetic risk factors examined in this study are only a part of the story and there are many facets of IBD that remain to be explained. Research will continue apace.